Random Matrix approach to collective behavior and bulk universality in protein dynamics

Covariance matrices of amino acid displacements, commonly used to characterize the large-scale movements of proteins, are investigated through the prism of Random Matrix Theory. Bulk universality is detected in the local spacing statistics of noise-dressed eigenmodes, which is well described by a Brody distribution with parameter $\beta\simeq 0.8$. This finding, supported by other consistent indicators, implies a novel quantitative criterion to single out the collective degrees of freedom of the protein from the majority of high-energy, localized vibrations.Comment: 4 pages, 7 figure

Fluctuations, Finite-Size Effects and the Thermodynamic Limit in Computer Simulations: Revisiting the Spatial Block Analysis Method

The spatial block analysis (SBA) method has been introduced to efficiently extrapolate thermodynamic quantities from finite-size computer simulations of a large variety of physical systems. In the particular case of simple liquids and liquid mixtures, by subdividing the simulation box into blocks of increasing size and calculating volume-dependent fluctuations of the number of particles, it is possible to extrapolate the bulk isothermal compressibility and Kirkwood–Buff integrals in the thermodynamic limit. Only by explicitly including finite-size effects, ubiquitous in computer simulations, into the SBA method, the extrapolation to the thermodynamic limit can be achieved. In this review, we discuss two of these finite-size effects in the context of the SBA method due to (i) the statistical ensemble and (ii) the finite integration domains used in computer simulations. To illustrate the method, we consider prototypical liquids and liquid mixtures described by truncated and shifted Lennard–Jones (TSLJ) potentials. Furthermore, we show some of the most recent developments of the SBA method, in particular its use to calculate chemical potentials of liquids in a wide range of density/concentration conditions

Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones

Owning the problem: Media portrayals of overweight dogs and the shared determinants of the health of human and companion animal populations

Weight-related health problems have become a common topic in Western mass media. News-coverage has also extended to overweight pets, particularly since 2003 when the U.S. National Academy of Sciences announced that obesity was also afflicting co-habiting companion animals in record numbers. To characterize and track views in popular circulation on causes, consequences and responsibilities vis-à-vis weight gain and obesity, in pets as well as in people, this study examines portrayals of overweight dogs that appeared from 2000 through 2009 in British, American and Australian mass media. The ethnographic content analysis drew inspiration from the literature in population health, animal-human relationships, communication framing and the active nature of texts in cosmopolitan societies. Three main types of media articles about overweight dogs appeared during this period: 1) reports emphasizing facts and figures; 2) stories emphasizing personal prescriptions for dog owners, and 3) societal critiques. To help ordinary people make sense of canine obesity, media articles often highlight that dogs share the lifestyle of their human companion or owner, yet the implications of shared social and physical environments is rarely considered when it comes to solutions. Instead, media coverage exhorts people who share their lives with overweight dogs to ‘own the problem’ and, with resolve, to normalize their dog’s physical condition by imposing dietary, exercise and relationship changes, thereby individualizing culpability rather than linking it to broader systemic issues. Keywords: Companion animals; Media; Narrative analysis; Obesity; Public understandin

Effectiveness and safety of bimekizumab for the treatment of plaque psoriasis. a real-life multicenter study—IL PSO (Italian landscape psoriasis)

Introduction: Bimekizumab is a monoclonal antibody that targets Interleukin-17 A and F, approved for the treatment of moderate-to-severe plaque psoriasis. While bimekizumab has been evaluated in several phase-III clinical trials, real-world evidence is still very limited. Method: This multicenter retrospective study included patients affected by plaque psoriasis treated with bimekizumab from May 1, 2022 to April 30, 2023, at 19 Italian referral hospitals. Patients affected by moderate-to-severe plaque psoriasis eligible for systemic treatments were included. The effectiveness of bimekizumab was evaluated in terms of reduction in psoriasis area and severity index (PASI) compared with baseline at weeks 4 and 16. The main outcomes were the percentages of patients achieving an improvement of at least 75% (PASI75), 90% (PASI90) and 100% (PASI100) in PASI score. Results: The study included 237 patients who received at least one injection of bimekizumab. One hundred and seventy-one patients and 114 reached four and 16 weeks of follow-up, respectively. Complete skin clearance was achieved by 43.3% and 75.4% of patients at weeks 4 and 16, respectively. At week 16, 86.8% of patients reported no impact on their quality of life. At week 16, there were no significant differences between bio-naïve and bio-experienced patients in terms of PASI75, PASI90 and PASI100. The most commonly reported adverse events (AEs) were oral candidiasis (10.1%). No severe AEs or AEs leading to discontinuation were observed throughout the study. Conclusion: Our experience supports the effectiveness and tolerability of bimekizumab in a real-world setting with similar results compared with phase-III clinical trials

Mechanical and Assembly Units of Viral Capsids Identified via Quasi-Rigid Domain Decomposition

Key steps in a viral life-cycle, such as self-assembly of a protective protein container or in some cases also subsequent maturation events, are governed by the interplay of physico-chemical mechanisms involving various spatial and temporal scales. These salient aspects of a viral life cycle are hence well described and rationalised from a mesoscopic perspective. Accordingly, various experimental and computational efforts have been directed towards identifying the fundamental building blocks that are instrumental for the mechanical response, or constitute the assembly units, of a few specific viral shells. Motivated by these earlier studies we introduce and apply a general and efficient computational scheme for identifying the stable domains of a given viral capsid. The method is based on elastic network models and quasi-rigid domain decomposition. It is first applied to a heterogeneous set of well-characterized viruses (CCMV, MS2, STNV, STMV) for which the known mechanical or assembly domains are correctly identified. The validated method is next applied to other viral particles such as L-A, Pariacoto and polyoma viruses, whose fundamental functional domains are still unknown or debated and for which we formulate verifiable predictions. The numerical code implementing the domain decomposition strategy is made freely available

Moderate exercise may attenuate some aspects of immunosenescence

BACKGROUND: Immunosenescence is related to the deterioration of many immune functions, which may be manifested in increased susceptibility to infection, cancer, and autoimmunity. Lifestyle factors, such as diet or physical activity, may influence the senescence of the immune system. It is widely accepted that moderate physical activity may cause beneficial effects for physical and psychological health as well as for the immune system activity in aged people. METHODS: Thirty elderly women aged 62 to 86 were subjected to a two-years authorized physical activity program. Peripheral blood lymphocytes distribution and the production of cytokines involved in the immune response development and regulation (IL-2, IL-4 and IFN-γ) were investigated. The same parameters were evaluated in two control groups of women: a sedentary group of 12 elderly women selected for the second round of the physical activity program and in a group of 20 sedentary young women. Flow cytometry methods were used for the examination of surface markers on peripheral blood lymphocytes and intracellular cytokines expression. RESULTS: The distribution of the main lymphocytes subpopulations in the peripheral blood of elderly women did not show changes after long-term moderate physical training. The percentage of lymphocytes expressing intracellular IL-2 was higher in the group of women attending 2-years physical activity program than in the control group of elderly sedentary women, and it was similar to the value estimated in the group of young sedentary women. There was no difference in the intracellular expression of IL-4 and IFN-γ between the active and elderly sedentary women. CONCLUSIONS: Our results suggest that moderate, long-term physical activity in elderly women may increase the production of IL-2, an important regulator of the immune response. This may help ameliorate immunosenescence in these women

The Italian Consensus Conference on FAI Syndrome in Athletes (Cotignola Agreement)

Background. Femoro-acetabular impingement (FAI) is an important topic in literature because of its strong relationship with sport populations. Methods. Sixty-five experts participated in "this Consensus Conference (CC)". They discussed, voted and approved a consensus document on the FAI syndrome in athletes. Results. The CC experts approved document provided suggestions concerning: 1) Epidemiology of FAI; 2) Clinical evaluation; 3) Radiological evaluation; 4) Conserva-tive treatment; 5) Surgical criteria; 6) Surgical techniques; 7) Post-surgical rehabilita-tion; 8) Outcome evaluation; 9) FAI-associated clinical frameworks. Conclusions. The CC offers a multidisciplinary approach to the diagnosis and treat-ment of FAI syndrome in athletes taking into account all the different steps needed to approach this pathology in sport populations